Synthesis of new camptothecin analogs with improved antitumor activities

  • Bioorg Med Chem Lett. 2009 Apr 1;19(7):2018-21. doi: 10.1016/j.bmcl.2009.02.031.
Satoshi Niizuma  1 ,  Masao Tsukazaki ,  Hitomi Suda ,  Takeshi Murata ,  Jun Ohwada ,  Sawako Ozawa ,  Hiroshi Fukuda ,  Chikako Murasaki ,  Masami Kohchi ,  Kenji Morikami ,  Kiyoshi Yoshinari ,  Mika Endo ,  Masako Ura ,  Hiromi Tanimura ,  Yoko Miyazaki ,  Tsuyoshi Takasuka ,  Akira Kawashima ,  Eitaro Nanba ,  Kounosuke Nakano ,  Kotaro Ogawa ,  Kazuko Kobayashi ,  Hisafumi Okabe ,  Isao Umeda ,  Nobuo Shimma
Affiliations
  • 1. Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
PMID: 19254843 DOI: 10.1016/j.bmcl.2009.02.031
Abstract

Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the Topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human Cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.

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